5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acids useful as intermediates for 5-HT3 antagonists

ABSTRACT

This invention provides bicyclic carboxylic esters and amides, their pharmaceutical formulations, and a method for their use in treating migraine, emesis, gastrointestinal disorders, schizophrenia, or anxiety in mammals.

CROSS-REFERENCE

This application is a continuation of application Ser. No. 07/222,466,filed on July 21, 1988, now abandoned which is a continuation-in-part ofcopending application U.S. Ser. No. 07/094,360, filed Sept. 8, 1987, nowabandoned.

BACKGROUND OF THE INVENTION

A variety of agents are presently under development as potentialtreatments for migraine headaches. For example, MDL-72222 (tropine3,5-dichlorobenzoate) is reported to block the M-receptors for5-hydroxytryptamine (5-HT), now referred to as 5-HT₃ receptors, therebyproviding an antimigraine effect--see Bradley, et al.,Neuropharmacology, 25(6), 563 (1986). Other 5-HT₃ antagonists reportedin the literature include Beecham compound 112-574, included in EPOpatent application Publication No. 158,265, and Merrell-Toraude compound105-834, (U.S. Pat. No. 4,486,441). All of these compounds are tropineor tropine-like esters or amides of a substituted benzoic acid.

Indole and related bicyclic derivatives are also reported to beanti-migraine agents. See, e.g., GB No. 2,125,398. Other bicyclicderivatives are reported in WO 84/03281 to have dopamine antagonistactivity and to be useful for lowering blood pressure and treatingemesis.

This invention provides potent specific 5-HT₃ antagonists useful fortreating migraine and emesis. The compounds are potent, orally active,and provide a long duration of effect.

SUMMARY OF THE INVENTION

This invention provides compounds of the Formula I ##STR1## andpharmaceutically acceptable acid addition salts thereof: wherein

R_(a) and R_(b) are independently hydrogen, methyl, or ethyl, or whentaken together with the carbon atom to which they are attached form a C₃-C₆ cycloalkyl ring, provided that R_(a) and R_(b) may not both behydrogen at the same time;

E is O, NH, or S;

R₁ and R.sbsb.1a are independently hydrogen, methyl, halo, C₁ -C₃alkoxy, (C₁ -C₃ alkyl)-S(O)_(t) --, trifluoromethyl, amino, hydroxy,(CH₃)₂ NSO₂ --, or (C₁ -C₄ alkyl)CONH--;

m is 1 or 2;

t is 0, 1, or 2;

Z is O or NH; and

R₂ is quinuclidine, quinuclidine N-oxide, 1-azabicyclo[3.3.1]non-4-yl,##STR2## wherein

R₃ is C₁ -C₃ alkyl, p and q are independently 0-2; Q is O or S; n is 0or 1; one of R₄ and R₅ when n is 0 is C₁ -C₄ alkoxy, C₁ -C₄alkoxycarbonyl, hydroxy, or C₁ -C₄ alkyl optionally substituted byhydroxy, C₁ -C₄ alkoxy, or C₁ -C₄ acyloxy and the other of R₄ and R₅ ishydrogen or C₁ -C₄ alkyl; one of R₄, R₅, and R₆ when n is 1 is C₁ -C₄alkyl and the other two of R₄, R₅, and R₆ are independently hydrogen orC₁ -C₄ alkyl.

Further provided by this invention is a method of treating migraine,emesis, gastrointestinal disorders, schizeophrenia, or anxiety in amammal which comprises administering to said mammal an effective amountof a compound of Formula I.

Also provided by this invention is a pharmaceutical compositioncomprising a compound of this invention in combination with apharmaceutically acceptable carrier, diluent or excipient.

This invention also provides aryl carboxylic acid compounds of theFormula IIa ##STR3## wherein

m is 1 or 2;

E is O, NH or S, and R₁ is hydrogen, methyl, halo, trifluoromethyl, (C₁-C₃ alkyl)-S(O)_(t) --, or methoxy. These compounds are useful asintermediates in preparing some of the pharmaceutically useful compoundsof this invention.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

Many of the functionalities and substituents part of R₂ are similarlyprovided in WO 84/03281 and the definitions of the substituents aspresently employed, to the extent consistent in scope with that found inthe reference, are considered to be identical as reported therein.

The term "C₃ -C₆ cycloalkyl ring" refers to cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. The term "C₁ -C₃ alkoxy" refers to methoxy,ethoxy, propoxy, or isopropoxy. The term "C₁ -C₄ alkyl" refers tomethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, andtert-butyl and includes within its definition the term "C₁ -C₃ alkyl".The term "halo" includes fluoro, chloro, and bromo.

The preferred compounds of this invention are those of Formula Ia##STR4## wherein

m is 1 or 2, R₁ ' is hydrogen, methyl, fluoro, bromo, or especiallychloro, R₂ ' is a tropane ring, i.e., an endo (or 3α)8-methyl-8-azabicyclo[3.2.1]oct-3-yl group, quinuclidine, i.e.,1-azabicyclo[2.2.2]oct-3-yl, orendo-9-methyl-9-azabicyclo[3.3.1]non-3-yl.

The pharmaceutically acceptable acid addition salts of this inventionare addition salts with suitable acids, such as those with inorganicacids, for example hydrochloric, hydrobromic, nitric, sulfuric, orphosphoric acids, or with organic acids, such as organic carboxylicacids, for example glycolic, maleic, hydroxymaleic, malic, tartaric,citric, lactic, and the like, or organic sulfonic acids, for example,methanesulfonic, ethanesulfonic, p-toluenesulfonic, ornaphthalene-2-sulfonic acids. In addition to the pharmaceuticallyacceptable salts listed above, other acid addition salts, such as thoseobtained with picric or oxalic acid, may serve as intermediates usefulin the purification of the compounds of this invention or in thepreparation of other, for example, pharmaceutically acceptable, acidaddition salts. In addition, these salts may also be useful foridentification or characterization of the compounds of this invention.

Also contemplated within the scope of the present invention are hydratesof the compounds or their various salts, or other solvates, such as thatformed with ethanol or other non-toxic solvents.

It is appreciated that when R_(a) and R_(b) are different, or when R₄,R₅ or R₆ are other than hydrogen, various stereoisomers are possible.Similarly, the R₂ ring may be in the α- or β- position. This inventionincludes all individual isomers and the various mixtures thereof.

The compounds of the present invention are prepared according toScheme 1. ##STR5## where X is OH or a carboxylic acid activating groupsuch as chloro, bromo, C₁ -C₄ acyloxy (a mixed anhydride), and the like.

The reaction between II, where X is an activating group, and III is wellknown in the art as demonstrated in U.S. Pat. No. 4,486,441, EPO patentapplication publication No. 158,265, and WO 84/03281, which referencesare expressly incorporated into this application. Preferably, thecarboxylic acid (II, X is OH) is converted to the corresponding acidchloride (II, X is --Cl) upon treatment with an excess of a reagent suchas thionyl chloride. When thionyl chloride is employed, it is preferablyused both as the reagent and as solvent. The reaction mixture is usuallyheated at reflux for 1-3 hours to bring the reaction to completion. Theresulting acid chloride is then treated with the appropriate amine oralcohol III. Usually, a 1- to 2-fold molar excess of III is employed. Inaddition, an inert solvent, such as toluene, is preferably used as amore convenient means of allowing the reaction to proceed. When asolvent is used, the mixture is preferably heated at reflux and under aninert atmosphere to drive the reaction to completion. Other variationsof this process, including different concentrations, molar proportions,solvents, etc. will be apparent to those skilled in the art. Forexample, one may employ peptide coupling reagents, such as1,1'-carbonyldiimidazole, with the carboxylic acid of Formula II,followed by introduction of III to the reaction mixture.

The general chemistry for preparing intermedaites II and III is wellknown in the art. In particular, many of the amines of Formula III areemployed in WO 84/03281. These and other necessary intermediates areeither commercially available, known in the literature, or can beprepared by methods known in the art.

In addition, the preparation of intermediates II is similar to thattaught in WO 84/03281. The preferred method of preparing the2,2-dimethyl 6.5 bicyclic compounds is provided in Scheme 2 whichfollows. ##STR6## wherein one of G and Y is O and the other is S, and E"is O or NH.

Accordingly to Scheme II, the phenol or aniline of Formula IV isalkylated with 2-methyl-2-propenyl bromide or chloride to provideintermediate V. This transformation is usually accomplished by heatingnear equimolar amounts of the two reagents together with an acidscavenger, such as potassium carbonate, and an inert solvent, such asacetone, at temperatures from about ambient temperature up to the refluxtemperature of the reaction mixture. The alkylated intermediate V isthen subjected to a Claisen rearrangement to provide the phenol oraniline of Formula VI. This rearrangement is accomplished by heating Vto temperatures of about 150°-200° C., preferably in a non-reactivesolvent such as 1-methyl-2-pyrrolidinone.

In order to prepare the dihydrobenzothiophenes of this invention,intermediate VI (E"=O) is treated with dimethylthiocarbamoyl chloride toprovide VII (G=O; Y=S). This transformation involves a standardacylating procedure which commonly uses a strong base, such as sodiumhydride, and a non-reactive solvent, such as dimethylformamide. Whenheated neat at 220°-230° C. for approximately 10 minutes, this thionicacid derivative rearranges to provide the corresponding thiolicintermediate VII (G=S; Y=O) which, upon treatment with base, such assodium hydroxide, provides the free thiol derivative VIII (E=S). Thishydrolysis potentially also hydrolyzes the ester which can bereesterified by conventional means. Alternatively, the acid analogue ofVIII (E=S) may be used for the subsequent cyclization.

The conversion of VIII to the bicyclic ester II (X=OCH₃) can beaccomplished by heating with 90% formic acid at reflux temperatures for2-3 hours. As mentioned above, in the special case where E is S, thetransformation can be accomplished either on the carboxylic acid orester upon treatment with an alcohol, such as methanol or ethanol, whichis saturated with hydrogen chloride gas. This transformation not onlyresults in ring closure, but also reesterifies the free acid. Thislatter transformation is most efficient when the reaction mixture isallowed to reflux for 16-20 hours.

Alternatively, the intermediate of Formula VIII can be treated withhydrogen bromide in a nonreactive solvent such as chloroform to preparethe corresponding alkyl bromide intermediate which can be isolated orused in situ to prepare II (X=OH) upon treatment with alcoholic sodiumor potassium hydroxide. See, e.g., U.S. Pat. No. 3,860,619.

The esters of Formula II are transformed into the carboxylic acidintermediates (II, X=OH) by standard methods of hydrolysis. Typically,the treatment of the ester with an aqueous solution of an inorganicbase, such as potassium or sodium hydroxide, is sufficient to convertthe ester to the free acid when allowed to reflux for 2-3 hours. Othermethods of effecting this transformation are readily apparent to thoseskilled in the art.

The related 6.6 bicyclic systems and alkyl variations of R_(a) and R_(b)can be prepared by methods analogous to that taught in Scheme 2 aboveemploying the appropriate starting materials, by other means such as aredescribed below, or are provided in the art, such as WO 84/03281.

Other transformations and intraconversions of the compounds of thisinvention can be accomplished. For example, amino groups may beintroduced onto the benzene portion of the bicyclic moiety either asintermediates such as Formulas II and IIa or final products of FormulaI. Typically, one or two nitro groups are introduced by direct nitrationof the intermediate or final product employing a mixture of nitric andsulfuric acids. The transformation of a nitro group into an amine isreadily accomplished by hydrogenation, for example, in the presence of a5% palladium-on-carbon catalyst in a non-reactive solvent such as ethylacetate. One or two nitro groups may be introduced either at the sametime or sequentially, i.e., a second nitro group may be introduced afterthe first has been transformed into the amine.

Halo groups may also be directly introduced at the intermediate or finalproduct stage. Typically, this can be accomplished by treating theintermediate or final product with a halogenating reagent such asiodobenzene dichloride in pyridine or some like halogenating reagent. Inlike manner, a halogen group can be removed from an intermediate orfinal product to form the comparable hydrogen-substituted derivative.This is best accomplished by subjecting the intermediate or finalproduct to hydrogenation conditions.

Other transformations and interconversions will be apparent to oneskilled in the art. For example, hydroxy-substituted compounds can beprepared from the corresponding alkoxy, particularly the methoxy,substituted intermediates or final products by dealkylating with anappropriate reagent. A preferred such reagent is the use of moltenpyridine hydrochloride which is very effective for effecting thistransformation. In like manner, an N,N-dimethylsulfonamido group can beintroduced onto the benzene ring of the bicycle by treating theprecursor intermediate or final product with chlorosulfonic acid in aninert solvent such as ethylene dichloride at low temperature followed bytreatment with dimethylamine. As will be appreciated by the skilledartisan, the particular sequence for effecting such transformations canbe determined depending upon the particular substituent and position ofthe substituent desired.

One additional transformation involves the use of a blocking group onthe R₂ portion of the molecule which can be removed and the resultingsecondary amino group realkylated to provide a compound of the presentinvention. For example, those R.sbsb.2a, R.sbsb.2b, and R.sbsb.2canalogues wherein R₃ is benzyl can be introduced into the final productto provide the corresponding N-benzyl cognate. The N-benzyl group may beremoved by standard means, such as by subjecting the intermediate tohydrogenation conditions. The resulting secondary amine can then bealkylated with the appropriate C₁ -C₄ alkyl halide in an inert solventsuch as tetrahydrofuran or isopropyl alcohol, optionally in the presenceof an acid scavenger such as sodium carbonate. Other such blockinggroups and means for deblocking will be apparent to those skilled inthis art.

The thio derivatives and intermediates of this invention (t is 0) may betransformed into the corresponding sulfoxide (t is 1) compounds upontreatment with a mild oxidizing agent, such as hydrogen peroxide inmethanol, meta-chloroperbenzoic acid (MCPBA) in methylene chloride at 0°C., or an alkali metal periodate in aqueous alcohol. The correspondingsulfones (t is 2) are prepared from the thio or sulfoxide compounds ontreatment with a strong oxidizing agent such as hydrogen peroxide inacetic acid or m-chloroperbenzoic acid in methylene chloride at 20°-30°C.

Intermediates IV, and other reagents necessary for preparing theintermediates and compounds of this invention, are commerciallyavailable, are known in the literature, or can be prepared by knownmethods. In addition, those skilled in the art will recognize thatvariations on the methods for preparing the claimed intermediates andcompounds as described above may be performed without detracting fromthe synthesis of these compounds. For example, other esters may beemployed, as may protecting groups, precursors, the direct introductionof the carboxylic acid group onto the phenyl ring of the bicycle(Kolbe-Schmitt reaction) etc. Moreover, certain R₁ substituents may beintroduced directly onto the phenyl ring. For example, a chloro groupcan be introduced by treating with iodobenzene, chlorine, and pyridine(See Murakami et al., Chem. Pharm. Bull. 19, 1696 (1971)) orN-chlorosuccinimide in dimethylformamide (U.S. Pat. No. 4,623,657).

The spirocycloalkyl compounds of this invention can be prepared in anumber of ways, such as that provided in Scheme 3: ##STR7## where w is1-4. This procedure is generally described in U.S. Pat. No. 4,329,459which is incorporated herein by reference. The reaction is a doubleGrignard synthesis and introduces the spiro ring onto the bicyclicnucleus. The intermediate XI can then be carboxylated as describedearlier.

In the special case of W=1 (the spirocyclopropyl compounds), the ketoneof formula IX can be transformed into the corresponding exomethylenecompound by any of a variety of procedures, such as thetitanium-aluminum complex method of Pine, et al., J.A.C.S., 102(9), 3270(1980). This exomethylene derivative can then be converted into thespirocyclopropyl compound by treatment with diiodomethane andzinc-copper by the procedure of Simmons and Smith, J.A.C.S., 81, 4256(1959). See also Organic Reactions, 20, Chapter 1, page 109.

The tricyclic compounds of formula XI can also be preparted according toU.S. Pat. No. 4,623,657, or obvious variations thereof. An illustrativeexample employing the chemistry of this reference is provided in Scheme4. ##STR8##

The following examples further illustrate the preparation of theintermediates and compounds of this invention. The examples areillustrative only and are not intended to limit the scope of theinvention in any way. Where structures were confirmed by infrared,proton nuclear magnetic resonance, or mass spectral analysis, thecompound is so designated by "IR", "NMR", or "MS", respectively.

EXAMPLE 1 2,2-dimethyl-2,3-dihydrobenzothiophene-7-carboxylic acid

A. Preparation of 2-(2-methyl-2-propenyloxy)benzoic acid, methyl ester.

A mixture of 152 g of methyl salicylate, 99 g of3-chloro-2-methylpropene, 151.8 g of potassium carbonate, and 500 ml ofacetone was heated at reflux overnight. After cooling, the mixture wasextracted with diethyl ether and ethyl acetate. The organic extractswere combined, washed twice with a 10% sodium chloride solution andwater, dried over sodium sulfate, and concentrated in vacuo. Theresulting liquid was vacuumed distilled. The fraction collected at120°-121° C. and 1.5 torr provided 76.2 g of the desired subtitleintermediate. NMR, MS.

Analysis for C₁₂ H₁₄ O₃ : Calc.: C, 69.89; H, 6.84; Found: C, 70.02; H,6.93.

B. Preparation of 2-hydroxy-3-(2-methyl-2-propenyl)benzoic acid, methylester.

A solution of 76.2 g of the intermediate of Example 1A above was heatedat reflux for 6 hours in 150 ml of 1-methyl-2-pyrrolidinone. The mixturewas then vacuum distilled and the fraction collected at 104°-109° C. and1.2 torr provided 60.6 g of the desired subtitle intermediate. MS.

Analysis for C₁₂ H₁₄ O₃ : Calc.: C, 69.89; H, 6.84; Found: C, 69.87; H,6.89.

C. Preparation of2-[dimethylamino(thioxomethyl)oxy]-3-(2-methyl-2-propenyl)benzoic acid,methyl ester.

To 1 liter of dry dimethylformamide were added 16 g of 60% sodiumhydride in oil. After stirring under a nitrogen atmosphere, 81.7 g of2-hydroxy-3-(2-methyl-2-propenyl)benzoic acid, methyl ester, as asolution in dimethylformamide, were added in dropwise fashion. Afterstirring at room temperature, a solution 49.6 g of dimethylthiocarbamoylchloride in dimethylformamide was added over a one hour period. Thereaction mixture was stirred at room temperature overnight, then pouredonto ice and extracted with diethyl ether and ethyl acetate. Thecombined organic extracts were washed successively with a 10% sodiumhydroxide solution and water, dried over sodium sulfate, andconcentrated in vacuo. The residue was vacuum distilled, and thefraction distilling at 162°-168° C. and 0.6 torr provided 69.9 g of thedesired subtitle intermediate. NMR, MS.

Analysis for C₁₅ H₁₉ NO₃ S: Calc.: C, 61.41; H, 6.53; N, 4.77; Found: C,64.87; H, 7.45; N, 4.37.

D. Preparation of2-[(dimethylamino)carbonylthio]-3-(2-methyl-2-propenyl)benzoic acid,methyl ester.

The intermediate from Example 1C above (69.5 g) was heated to 220°-230°C. for 10-15 minutes. After cooling, the residue was vacuum distilled.The fraction collected at 153°-155° C. and 0.1 torr and the remainingdistillation residue were combined and purified by high pressure liquidchromatography over silica gel eluting with 20% ethyl acetate intoluene. The appropriate fractions were combined and concentrated invacuo to provide 41.8 g of the desired subtitle intermediate. MS, IR,NMR.

Analysis for C₁₅ H₁₉ NO₃ S: Calc.: C, 61.41; H, 6.53; N, 4.77; Found: C,61.40; H, 6.30; N, 5.05.

E. Preparation of 2-mercapto-3-(2-methyl-2-propenyl)benzoic acid.

The 41.8 g of intermediate from Example 1D above were heated at refluxfor 18 hours with 175 ml of methanol and 12 g of sodium hydroxide. Thereaction mixture was poured into ice water and extracted with ethylacetate. The aqueous layer was made acidic with hydrochloric acid andextracted again with ethyl acetate. The organic layer was washed withwater, dried over sodium sulfate, and concentrated in vacuo providing28.8 g of desired subtitle intermediate, m.p. 89°-92° C. NMR, MS.

Analysis for C₁₁ H₁₂ O₂ S: Calc.: C, 63.43; H, 5.81; Found: C, 63.69; H,5.89.

F. Preparation of 2,2-dimethyl-2,3-dihydrobenzothiophene-7-carboxylicacid, methyl ester.

A mixture of 23.8 g of the intermediate from Example 1E above and 1liter of methanol was saturated with hydrogen chloride gas and thenrefluxed overnight. The solution was concentrated in vacuo, added towater, and extracted with ethyl acetate. The organic layer was washedwith water, dried over sodium sulfate, and concentrated in vacuo,providing 24.1 g of the desired subtitle intermediate as an oil. MS.

Analysis for C₁₂ H₁₄ O₂ S: Calc.: C, 64.83; H, 6.35; Found: C, 64.56; H,6.33.

G. Preparation of 2,2-dimethyl-2,3-dihydrobenzothiophene-7-carboxylicacid.

The 24.1 g of ester product from Example 1F above were heated at refluxwith 50 g of sodium hydroxide and 200 ml of water for 2-3 hours. Aftercooling, the mixture was extracted with diethyl ether and ethyl acetate.The aqueous layer was acidified with hydrochloric acid and againextracted with ethyl acetate and diethyl ether. These latter organicextracts were combined and washed with water, dried over sodium sulfate,and concentrated in vacuo. Crystallization of the resulting solid fromethyl acetate/hexane provided 8.8 g of the desired title intermediate,m.p. 179°-182° C. NMR, MS.

Analysis for C₁₁ H₁₂ O₂ S: Calc.: C, 63.43; H, 5.81; Found: C, 63.18; H,6.10.

EXAMPLES 2-14

The following compounds were prepared from the corresponding methylesters according to the procedure of Example 1G. The general preparationof the ester intermediates followed that of Examples 1A, 1B, and avariation of 1F wherein 90% formic acid was employed in place of thehydrogen chloride/methanol combination. 2-Monomethyl derivatives wereprepared according to the procedure of Example 1A using allyl bromide inplace of 3-chloro-2-methylpropene followed by subsequent transformationsin the same way. Yields are expressed as the molar percent yield fromthe ester except as indicated.

2. 2,2-Dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid, 82% yield (fromthe 2-methyl-2-propenyloxy intermediate), m.p. 135°-137° C. NMR, MS.

Analysis for C₁₁ H₁₂ O_(3:) Calc.: C, 68.74; H, 6.29; Found: C, 69.04;H, 6.47.

3. 2,2-Dimethyl-4-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, 87%yield, m.p. 195°-197° C.

Analysis for C₁₁ H₁₁ ClO₃ : Calc.: C, 58.29; H, 4.89; Found: C, 58.55;H, 4.76.

4. 2,2-Dimethyl-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, 71%yield (from the 2-methyl-2-propenylphenol intermediate), m.p.158.5°-160° C. NMR, MS.

Analysis for C₁₁ H₁₁ ClO₃ : Calc.: C, 58.29; H, 4.89; Found: C, 58.08;H, 4.65.

5. 2,2-Dimethyl-2,3-dihydrobenzofuran-5-carboxylic acid, 61% yield, m.p.174°-176° C. NMR, MS.

Analysis for C₁₁ H₁₂ O₃ : Calc.: C, 68.74; H, 6.29; Found: C, 68.51; H,6.34.

6. 2,2,5-Trimethyl-2,3-dihydrobenzofuran-7-carboxylic acid, 82% yield,m.p. 170°-172° C. NMR, MS.

Analysis for C₁₂ H₁₄ O₃ : Calc.: C, 69.89; H, 6.84; Found: C, 70.19; H,6.89.

7. 2,2-Dimethyl-2,3-dihydrobenzofuran-4-carboxylic acid, 66% yield (fromthe 2-methyl-2-propenylphenol intermediate), m.p. 174°-176° C. MS, NMR.

Analysis for C₁₁ H₁₂ O₃ : Calc.: C, 68.74; H, 6.29; Found: C, 68.89; H,6.25.

8. 2,2-Dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid, 80% yield, m.p.138°-141° C. NMR, MS.

Analysis for C₁₁ H₁₂ O₃ : Calc.: C, 68.74; H, 6.29; Found: C, 68.50; H,6.08.

9. 2-Methyl-5-methoxy-2,3-dihydrobenzofuran-7-carboxylic acid, 100%yield (from the 2-allylphenol intermediate via the bromo intermediate),m.p. 120°-121° C.

Analysis for C₁₁ H₁₂ O₄ : Calc.: C, 63.45; H, 5.81; Found: C, 63.22; H,5.87.

10. 2,2-Dimethyl-7-chloro-2,3-dihydrobenzofuran-5-carboxylic acid, 72%yield, m.p. 189°-190° C.

Analysis for C₁₁ H₁₁ ClO₃ : Calc.: C, 58.29; H, 4.89; Found: C, 58.40;H, 4.93.

11. 2-Methyl-5-fluoro-2,3-dihydrobenzofuran-7-carboxylic acid, 72%yield, m.p. 129.5°-131.5° C.

Analysis for C₁₀ H₉ OF₃ : Calc.: C, 61.23; H, 4.62; Found: C, 61.41; H,4.78.

12. 2-Methyl-2,3-dihydrobenzofuran-7-carboxylic acid, 88% yield (fromthe 2-(2-bromopropyl)phenol intermediate), m.p. 125°-127° C.

Analysis for C₁₀ H₁₀ O₃ : Calc.: C, 67.03; H, 6.19; Found: C, 67.23; H,5.99.

13. 2-Methyl-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, 21% yield(from the 2-(2-bormopropyl)phenol intermediate), m.p. 184°-188° C.

Analysis for C₁₀ H₉ ClO₃ : Calc.: C, 56.49; H, 4.27; Found: C, 56.56; H,4.38.

14. 2,2-Dimethyl-5-methoxy-2,3-dihydrobenzofuran-7-carboxylic acid, 68%yield, m.p. 140°-142° C.

Analysis for C₁₂ H₁₄ O₄ : Calc.: C, 64.85; H, 6.35; Found: C, 64.99; H,6.25.

EXAMPLE 15 2,2-Dimethylchroman-8-carboxylic acid

A. Preparation of 2-(3-methyl-3-hydroxybutyl)phenol.

To a solution of 200 ml of 3M methyl magnesium chloride intetrahydrofuran (THF) and 150 ml of THF was added a solution 44.4 g ofdihydrocoumarin in THF over a 40 minute period. An additional 150 ml ofTHF were added and, after cooling the resulting exotherm, the mixturewas stirred at room temperature overnight. The solution was cooled andtreated with 50 ml of a saturated ammonium chloride solution and 100 mlof water. After stirring one hour, the mixture was added to ice waterand extracted with diethyl ether. The organic layer was washed withwater, dried over sodium sulfate, and concentrated in vacuo to provide57.5 g of the desired subtitle intermediate, m.p. 113°-115° C.

B. Preparation of 2,2-dimethylchroman.

The 57.5 g of phenol from Example 15A above were dissolved in 320 ml ofacetic acid and 120 ml of 20% sulfuric acid and heated to reflux for 45minutes. The solution was cooled, added to ice, and extracted withdiethyl ether. The organic layer was washed with 200 ml of 10% sodiumhydroxide and water, dried over sodium sulfate, and concentrated invacuo. Vacuum distillation at 83°-85° C. and approximately 5 torrprovided 36.3 g of the desired subtitle intermediate.

C. Preparation of 2,2-dimethylchroman-8-carboxylic acid.

To a solution of 1.6M n-butyllithium in hexane and 150 ml of diethylether were added a solution of 27 g of 2,2-dimethylchroman in diethylether over a one hour period at room temperature. The solution was thenheated at reflux 160 minutes, cooled, and poured into dry ice/diethylether. The mixture was allowed to come to room temperature, poured intoice water, and layers separated. The organic layer was washed withwater, dried over sodium sulfate, and concentrated in vacuo to provide21 g of solid. The aqueous layer was acidified and the resultingprecipitate extracted into diethyl ether/ethyl acetate. The organicextract was washed with water, dried over sodium sulfate, andconcentrated in vacuo to provide 9 g of solid. The two isolated solidswere combined and chromatographed over silica gel eluting with 10% ethylacetate in toluene. The appropriate fractions were combined andconcentrated in vacuo to provide 9.8 g of the desired titleintermediate, m.p. 90°-92° C.

Analysis for C₁₂ H₁₄ O₃ : Calc.: C, 69.89; H, 6.84; Found: C, 69.84; H,7.12.

EXAMPLE 16Endo-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)benzo[b]thiophene-7-carboxamide(Z)-2-butenedioate

A mixture of 8.8 g of2,2-dimethyl-2,3-dihydrobenzothiophene-7-carboxylic acid and 119 g ofthionyl chloride was heated at reflux for 3 hours. After the mixture wasconcentrated in vacuo and azeotroped with toluene, dry toluene was addedand the solution cooled to 5° C. A solution of 7 g of tropamine intoluene was added in dropwise fashion and the reaction heated at refluxovernight. After cooling, the mixture was added to ice water, madebasic, and extracted with diethyl ether/ethyl acetate. The organic layerwas washed twice with 6N hydrochloric acid. The combined aqueousextracts were cooled, made basic with sodium hydroxide solution, andextracted with ethyl acetate. The ethyl acetate solution was washedtwice with water, dried over sodium sulfate, and concentrated in vacuoproviding 11.6 g of the title product free base as an oil. The maleatesalt was then prepared and crystallized from ethanol/diethyl ether/ethylacetate providing 11.5 g of the desired title product, m.p. 197°-199° C.NMR, MS.

Analysis for C₂₃ H₃₀ N₂ O₅ S: Calc.: C, 61.86; H, 6.77; N, 6.27; Found:C, 61.58; H, 6.84; N, 6.10.

EXAMPLES 17-42

The following products were prepared from the corresponding carboxylicacid via the acid chloride according to the procedure of Example 16employing the appropriate amine or alcohol derivative of tropane.

17.Endo-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide(Z)-2-butenedioate, 61% yield, m.p. 163°-164° C.

Analysis for C₂₃ H₃₀ N₂ O₆ : Calc.: C, 64.17; H, 7.02; N, 6.51; Found:C, 64.20; H, 7.25; N, 6.29.

18. Endo-4-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 100% yield,m.p. 198°-200° C.

Analysis for C₂₃ H₂₉ ClN₂ O₆ : Calc.: C, 59.42; H, 6.29; N, 6.03; Found:C, 59.58; H, 6.38; N, 6.23.

19. Endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1.]oct-3-yl-7-benzofurancarboxamide (Z)-2-butenedioate, 74% yield,m.p. 184°-186° C.

Analysis for C₂₃ H₂₉ ClN₂ O₆ : Calc.: C, 59.42; H, 6.29; N, 6.03; Found:C, 59.23; H, 6.18; N, 6.14.

20.Endo-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-5-benzofurancarboxamide(Z)-2-butenedioate, 83% yield, m.p. 193°-195° C.

Analysis for C₂₃ H₃₀ N₂ O₆ : Calc.: C, 64.17; H, 7.02; N, 6.51; Found:C, 63.89; H, 6.85; N, 6.42.

21.Endo-2,3-dihydro-2,2,5-trimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide(Z)-2-butenedioate, 65% yield, m.p. 173°-174° C.

Analysis for C₂₄ H₃₂ N₂ O₆ : Calc.: C, 64.85; H, 7.26; N, 6.03; Found:C, 64.59; H, 7.41; N, 6.29.

22. Endo-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-4-benzofurancarboxamide (Z)-2-butenedioate, 27% yield,m.p. 182°-184° C.

Analysis for C₂₃ H₃₀ N₂ O₆ : Calc.: C, 64.17; H, 7.03; N, 6.51; Found:C, 63.95; H, 6.80; N, 6.72.

23.Endo-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-6-benzofurancarboxamide(Z)-2-butenedioate, 43% yield, m.p. 174°-176° C.

Analysis for C₂₃ H₃₀ N₂ O₆ : Calc.: C, 64.17; H, 7.02; N, 6.51; Found:C, 64.11; H, 6.97; N, 6.52.

24. Endo-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylic acid,8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester (Z)-2-butenedioate, 51%yield, m.p. 174°-176° C.

Analysis for C₂₃ H₂₉ NO₇ : Calc.: C, 64.02; H, 6.77; N, 3.25; Found: C,64.02; H, 6.79; N, 3.21.

25. Endo-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylic acid,8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester (Z)-2-butenedioate, 48%yield, m.p. 175°-177° C.

Analysis for C₂₃ H₂₈ ClNO₇ : Calc.: C, 59.29; H, 6.06; N, 3.01; Found:C, 59.19; H, 6.15; N, 2.93.

26. Exo-2,2-dimethyl-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid,8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester (Z)-2-butenedioate, 86%yield, m.p. 222°-224° C.

Analysis for C₂₃ H₂₈ ClNO₇ : Calc.: C, 59.29; H, 6.06; N, 3.01; Found:C, 59.42; H, 5.88; N, 2.81.

27. dl-endo-2,3-dihydro-5-methoxy-2-methyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 62% yield,m.p. 172°-174° C.

Analysis for C₂₃ H₃₀ N₂ O₇ : Calc.: C, 61.87; H, 6.77; N, 6.27; Found:C, 61.62; H, 6.81; N, 6.10.

28. dl-endo-2-methyl-5-methoxy-2,3-dihydro-7-benzofurancarboxylic acid,8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester (Z)-2-butenedioate, 22%yield, m.p. 162°-164° C.

Analysis for C₂₃ H₂₉ NO₈ : Calc.: C, 61.73; H, 6.53; N, 3.13; Found: C,61.45; H, 6.68; N, 3.35.

29. Endo-2,2-dimethyl-7-chloro-2,3-dihydro-5-benzofurancarboxylic acid,8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester (Z)-2-butenedioate, 20%yield, m.p. 154°-156° C.

Analysis for C₂₃ H₂₈ ClNO₇ : Calc.: C, 59.29; H, 6.06; N, 3.01; Found:C, 59.06; H, 6.31; N, 2.95.

30. Exo-2,2-dimethyl-5-chloro-2,3-dihydro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7benzofurancarboxamide (Z)-2-butenedioate, 63% yield,m.p. 129°-120.5° C.

Analysis for C₂₃ H₂₉ ClN₂ O₆ : Calc.: C, 58.28; H, 6.38; N, 5.91; Found:C, 58.65; H, 6.62; N, 5.72.

31. dl-endo-5-fluoro-2,3-dihydro-2-methyl-7-benzofurancarboxylic acid,8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester (Z)-2-butenedioate, 24%yield, m.p. 154°-156° C.

Analysis for C₂₂ H₂₆ FNO₇ : Calc.: C, 60.68; H, 6.02; N, 3.22; Found: C,60.94; H, 6.21; N, 3.30.

32. dl-endo-5-chloro-2,3-dihydro-2-methyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 31% yield,m.p. 196°-198° C.

Analysis for C₂₂ H₂₇ ClN₂ O₆ : Calc.: C, 58.60; H, 6.04; N, 6.21; Found:C, 58.88; H, 6.26; N, 6.17.

33.dl-endo-2,3-dihydro-2-methyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide(Z)-2-butenedioate, 43% yield, m.p. 144°-146° C.

Analysis for C₂₂ H₂₈ N₂ O₆ : Calc.: C, 63.45; H, 6.78; N, 6.73; Found:C, 63.72; H, 7.00; N, 6.75.

34. dl-endo-5-chloro-2,3-dihydro-2-methyl-7-benzofurancarboxylic acid,8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester (Z)-2-butenedioate, 18%yield, m.p. 170°-172° C.

Analysis for C₂₂ H₂₆ ClNO₇ : Calc.: C, 58.47; H, 5.80; N, 3.10; Found:C, 58.93; H, 6.02; N, 3.28.

35. dl-endo-2,3-dihydro-2-methyl-7-benzofurancarboxylic acid,8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester (Z)-2-butenedioate, 36%yield, m.p. 178°-179° C.

Analysis for C₂₂ H₂₇ NO₇ : Calc.: C, 63.30; H, 6.52; N, 3.36; Found: C,63.40; H, 6.76; N, 3.60.

36.Endo-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-8-chromancarboxamide(Z)-2-butenedioate, 39% yield, m.p. 172°-174° C.

Analysis for C₂₄ H₃₂ N₂ O₆ : Calc.: C, 64.85; H, 7.26; N, 6.30; Found:C, 64.62; H, 7.24; N, 6.22.

37. Endo-2,3-dihydro-2,2,5-trimethyl-7-benzofurancarboxylic acid,8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester (Z)-2-butenedioate, 36%yield, m.p. 167°-168° C.

Analysis for C₂₄ H₃₁ NO₇ : Calc.: C, 64.70; H, 7.01; N, 3.14; Found: C,64.46; H, 6.74; N, 2.95.

38.dl-exo-2,3-dihydro-2-methyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide(Z)-2-butenedioate, 48% yield, m.p. 134°-135° C.

Analysis for C₂₂ H₂₈ N₂ O₆ : Calc.: C, 63.45; H, 6.78; N, 6.73; Found:C, 63.15; H, 6.53; N, 6.47.

39.Exo-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide(Z)-2-butenedioate, 42% yield, m.p. 171°-173° C.

Analysis for C₂₃ H₃₀ N₂ O₆ : Calc.: C, 64.17; H, 7.02; N, 6.51; Found:C, 64.49; H, 7.10; N, 6.69.

40. dl-endo-2,3-dihydro-2,5-dimethyl-7-benzofurancarboxylic acid,8-methyl-8-azabicyclo[3.2.1]cot-3-yl ester (Z)-2-butenedioate, 6% yield,m.p. 161°-164° C.

Analysis for C₂₃ H₂₉ NO₇ : Calc.: C, 64.02; H, 6.77; N, 3.28; Found: C,64.24; H, 6.54; N, 3.52.

41. Endo-2,3-dihydro-2,2-dimethyl-5-methoxy-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 65% yield,m.p. 189°-190° C.

Analysis for C₂₄ H₃₂ N₂ O₇ : Calc.: C, 62.59; H, 7.00; N, 6.08; Found:C, 62.30; H, 7.17; N, 6.03.

42. Endo-5-fluoro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 50% yield,m.p. 178°-180° C.

Analysis for C₂₃ H₂₉ FN₂ O₆ : Calc.: C, 61.60; H, 6.52; N, 6.25; Found:C, 61.31; H, 6.77; N, 6.15.

EXAMPLES 43-46

The following intermediates were prepared in the same manner asdescribed for Examples 2-14.

43. 2,2-Dimethyl-2,3-dihydro-6-chlorobenzofuran-7carboxylic acid, 58%yield, m.p. 164°-166° C.

Analysis for C₁₁ H₁₁ ClO₃ : Calc.: C, 58.29; H, 4.89; Found: C, 58.15;H, 4.92.

44. 4-Amino-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylic acid, 71%yield (from the N-formyl derivative of the methyl ester), m.p. 166°-169°C.

Analysis for C₁₁ H₁₃ NO₃ : Calc.: C, 63.76; H, 6.32; N, 6.76; Found: C,63.48; H, 6.55; N, 6.85.

45. 2,2-Dimethyl-4-methoxy-2,3-dihydrobenzofuran-7-carboxylic acid, 69%yield, m.p. 174°-175° C.

Analysis for C₁₂ H₁₄ O₄ : Calc.: C, 64.85; H, 6.35; Found: C, 64.77; H,6.19.

46. 2,3-Dihydro-2,2-dimethyl-6-fluoro-7-benzofurancarboxylic acid, 74%yield, m.p. 143°-145° C.

Analysis for C₁₁ H₁₁ OF₃ : Calc.: C, 62.85; H, 5.27; Found: C, 62.87; H,5.13.

EXAMPLE 47

5-Amino-4-chloro-2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylic acid

A. Preparation of4-chloro-5-nitro-2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylic acid.

To a mixture of 40 ml of nitric acid and 40 ml of sulfuric acid cooledto 5° C. by means of an external ice bath were added 10 g of4-chloro-2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylic acid over aperiod of 28 minutes. After stirring at 5° C. for 10 minutes, themixture was added to ice with stirring. The resulting solid wascollected by filtration and washed with water. After air drying, theresidue was crystallized twice from ethyl acetate/hexane to provide 3.5g of the desired subtitle intermediate, m.p. 260°-262° C.

Analysis for C₁₁ H₁₀ ClNO₅ : Calc.: C, 48.64; H, 3.71; N, 5.16; Found:C, 48.36; H, 3.81; N, 5.30.

B. Preparation of5-amino-4-chloro-2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylic acid.

A mixture of 7.53 g of the nitro intermediate named in Example 47A abovein 150 ml of ethyl acetate was subjected to a hydrogen atmosphere for 16hours in the presence of 5% palladium on carbon. The reaction mixturewas filtered and the filtrate concentrated to give a residue which wascrystallized form ethyl acetate/hexane providing 5.1 g of the desiredtitle intermediate, m.p. 185°-187° C.

Analysis for C₁₁ H₁₀ ClNO₃ : Calc.: C, 55.13; H, 4.21; N, 5.84; Found:C, 54.91; H, 4.50; N, 5.61.

EXAMPLE 485-Chloro-4-methoxy-2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylic acid

A mixture of methyl4-methoxy-2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylate, 7.1 g ofpyridine, and 400 ml of tetrahydrofuran was cooled to -30° C. by meansof an external dry ice/acetone bath. A solution of 27.5 g of iodobenzenedichloride in 100 ml of dry tetrahydrofuran was added dropwise to themixture. After addition was complete, the reaction was stirred at roomtemperature overnight. The reaction mixture was concentrated in vacuo,water was added, and the mixture was steam distilled. To the residuewere added ethyl acetate and diethyl ether. The organic mixture waswashed with water, dried over sodium sulfate, and concentrated in vacuo.Eleven grams of this product were treated with 15 g of sodium hydroxideand 200 ml of water following the procedure of Example 1G above toprovide 7.6 g of the desired title intermediate, m.p. 165°-166.5° C.

Analysis for C₁₂ H₁₃ ClO₄ : Calc.: C, 56.15; H, 5.11; Found: C, 56.04;H, 5.21.

Following the same procedure, 19.9 g of methyl4-amino-2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylate was transformedinto 20.1 g of4-amino-5-chloro-2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylic acid,m.p. 176°-178° C.

Analysis for C₁₁ H₁₂ ClNO₃ : Calc.: C, 54.67; H, 5.01; N, 5.80; Found:C, 54.43; H, 5.22; N, 5.74.

EXAMPLES 49-58

The following compounds were prepared from the corresponding carboxylicacid and the appropriate amine via the acid chloride prepared from thethionyl chloride according to the procedure of Example 16 or asgenerated upon treatment with phosphorous trichloride.

49.2,3-Dihydro-5-chloro-2,2-dimethyl-N-(1-azabicyclo[2.2.2]oct-3-yl)-7-benzofurancarboxamide(Z)-2-butenedioate, 75% yield, m.p. 195°-197° C.

Analysis for C₂₂ H₂₇ ClN₂ O₆ : Calc.: C, 58.60; H, 6.04; N, 6.21; Found:C, 58.46; H, 6.01; N, 6.20.

50. Endo-2,2-dimethyl-2,3-dihydro-6-chloro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 70% yield,m.p. 198.5°-200° C.

Analysis for C₂₃ H₂₉ ClN₂ O₆ : Calc.: C, 59.42; H, 6.29; N, 6.03; Found:C, 59.16; H, 6.24; N, 5.96.

51. Endo-7-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-5-benzofurancarboxamide (Z)-2-butenedioate, 79% yield,m.p. 194°-196° C.

Analysis for C₂₂ H₂₉ ClN₂ O₆ : Calc.: C, 59.42; H, 6.29; N, 6.03; Found:C, 59.48; H, 6.23; N, 6.00.

52. Endo-2,3-dihydro-4-methoxy-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 50% yield,m.p. 194°-195° C.

Analysis for C₂₄ H₃₂ N₂ O₇ : Calc.: C, 62.59; H, 7.00; N, 6.08; Found:C, 62.80; H, 7.11; N, 6.09.

53.N-(1-azabicyclo[2.2.2]oct-3-yl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-8-carboxamide(Z)-2-butenedioate, 36% yield, m.p. 169°-170° C.

Analysis C₂₂ H₃₀ N₂ O₆ : Calc.: C, 64.17; H, 7.02; N, 6.51; Found: C,64.00; H, 7.03; N, 6.46.

54. Endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 20% yield,m.p. 175°-177° C.

Analysis for C₂₄ H₃₁ ClN₂ O₆ : Calc.: C, 60.18; H, 6.52; N, 58.4; Found:C, 60.42; H, 6.75; N, 6.03.

55.Endo-2,3-dihydro-2,2-dimethyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-7-benzofurancarboxamide(Z)-2-butenedioate, 36% yield, m.p. 153°-154° C.

Analysis for C₂₄ H₃₂ N₂ O₆ : Calc.: C, 65.48; H, 7.47; N, 6.11; Found:C, 65.25; H, 7.24; N, 6.01.

56.Endo-2,3-dihydro-4-amino-5-chloro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 45% yield,m.p. 211°-213° C.

Analysis for C₂₃ H₃₀ ClN₃ O₆ : Calc.: C, 57.56; H, 6.30; N, 8.76; Found:C, 57.42; H, 6.28; N, 8.63.

57.Endo-5-chloro-2,3-dihydro-4-methoxy-2,2-dimethyl-N-(8-methyl-8azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 49% yield,m.p. 179°-180° C.

Analysis for C₂₄ H₃₁ ClN₂ O₇ : Calc.: C, 58.24; H, 6.31; N, 5.66; Found:C, 57.96; H, 6.48; N, 5.78.

58. 5-Fluoro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 50% yield,m.p. 178°-180° C.

Analysis for C₂₃ H₂₉ FN₂ O₆ : Calc.: C, 61.60; H, 6.52; N, 6.25; Found:C, 61.31; H, 6.77; N, 6.15.

EXAMPLE 59Endo-5-[(dimethylamino)sulfonl]-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate

A. Preparation of5-[(dimethylamino)sulfonyl]-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylicacid.

Fifty-eight grams of chlorosulfonic acid was cooled to 10° C. and asolution of 19.2 g of 2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylicacid in 300 ml of methylene chloride was added slowly keeping thetemperature between 10°-15° C. When the addition was complete, themixture was stirred in the ice bath for two hours. The mixture was addedto ice water and the resulting white precipitate recovered byfiltration. The solid was added to approximately 200 ml of 40%dimethylamine in water which had been cooled to 10° C. After stirringovernight, the mixture was acidified with 6N hydrochloric acid. Theresulting white precipitate was recovered by filtration. The residue wascrystallized from ethyl acetate/hexane to provide 5.7 g of the desiredsubtitle intermediate, m.p. 211°-212° C.

Analysis for C₁₃ H₁₇ NSO₅ : Calc.: C, 52.16; H, 5.72; N, 4.68; Found: C,52.44; H, 5.79; N, 4.64.

B. Preparation ofendo-5-[(dimethylamino)sulfonyl]-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide(Z)-2-butenedioate.

The 5.7 g of the benzofurancarboxylic acid of Example 59A above wastransformed into the acid chloride and reacted with tropamine accordingto the procedure of Example 16 to provide 7.0 g of the desired titleproduct, m.p. 202°-203° C.

Analysis for C₂₅ H₃₅ N₃ SO₈ : Calc.: C, 55.85; H, 6.56; N, 7.82; Found:C, 55.93; H, 6.56; N, 7.65.

EXAMPLE 60 2,3-Dihydro-2,2-dimethyl-N-(1-azabicyclo[2.2.2]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate

A mixture of 2.4 g of2,3-dihydro-5-chloro-2,2-dimethyl-N-(1-azabicyclo[2.2.2]oct-3-yl)-7-benzofurancarboxamide,0.51 g of triethylamine, 0.3 g of 5% palladium on carbon, and 100 ml ofethanol were hydrogenated at 60 psi and 40°-50° C. overnight. Themixture was cooled, filtered, concentrated in vacuo, and converted intothe maleate salt. Crystallization from ethanol/diethyl ether provided2.0 g of desired title product, m.p. 182°-185° C.

Analysis for C₂₂ H₂₈ N₂ O₆ : Calc.: C, 63.45; H, 6.78; N, 6.73; Found:C, 63.58; H, 6.91; N, 6.86.

EXAMPLE 61 Endo-2,2-dimethyl-6-chloro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-8-chromancarboxamide (Z)-2-butenedioate

Following the general procedure of Example 48, 1.96 ofendo-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-8-chromancarboxamide(Z)-butenedioate 50 ml of chloroform, 1.02 ml of pyridine, and 1.24 g ofiodobenzene dichloride were allowed to react. After workup andcrystallization from ethanol/diethyl acetate, 350 mg of the desiredtitle product were isolated, m.p. 210°-211° C.

Analysis for C₂₄ H₃₁ ClN₂ O₆ : Calc.: C, 60.18; H, 6.52; N, 5.85; Found:C, 59.94; H, 6.47; N, 5.75.

EXAMPLE 62Endo-2,3-dihydro-5-hydroxy-2,2-dimethyl-N-(8-methyl-8azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate

A mixture of 1.4 g ofendo-2,3-dihydro-5-methoxy-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamideand 11.5 g of pyridine hydrochloride was heated under a nitrogenatmosphere at 180° C. for three hours. The molten mixture was poured hotover ice and stirred overnight. The solution was made basic with sodiumhydroxide, extracted with ethyl acetate, and carbon dioxide gas wasbubbled into the basic solution to adjust the pH. Extraction with ethylacetate and concentration of the organic solution provided a residuewhich was converted into the maleate salt. After crystallization fromethanol/diethyl ether, the title product (114 mg) was isolated, m.p.228°-231° C.

Analysis for C₂₃ H₃₀ N₂ O₇ : Calc.: C, 61.87; H, 6.77; N, 6.27; Found:C, 61.67; H, 7.00; N, 6.21.

EXAMPLE 63

The following benzyl derivatives were prepared from the correspondingacid chloride and the appropriate 8-benzyl-tropanamine derivative. Thesecompounds are useful as intermediates in that they may be deblocked (seeExample 64 which follows) and alkylated with the appropriate alkylatingagent to prepare the compounds of this invention. (See Example 65).

Endo-2,3-dihydro-2-methyl-N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 70% yield,m.p. 183°-184° C.

Analysis for C₂₈ H₃₂ N₂ O₆ : Calc.: C, 68.28; H, 6.55; N, 5.69; Found:C, 67.98; H, 6.54; N, 5.39.

Endo-2,3-dihydro-2,2-dimethyl-N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl-7-benzofurancarboxamide (Z)-2-butenedioate, 49% yield,m.p. 186°-187° C.

Analysis for C₂₉ H₃₄ N₂ O₆ : Calc.: C, 68.76; H, 6.77; N, 5.53; Found:C, 68.97; H, 6.94; N, 5.63.Endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl-7-benzofurancarboxamide, 59% yield.

Analysis for C₂₅ H₂₉ ClN₂ O₂ : Calc.: C, 70.66; H, 6.88; N, 6.59; Found:C, 70.39; H, 7.00; N, 6.43.

Exo-2-methyl-2,3-dihydro-N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 82%, m.p.125°-127° C.

Analysis for C₂₈ H₃₂ N₂ O₆ : Calc.: C, 68.28; H, 6.55; N, 5.67; Found:C, 68.00; H, 6.61; N, 5.47.

Exo-2,2-dimethyl-2,3-dihydro-N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 83% yield,m.p. 208.5°-210° C.

Analysis for C₂₉ H₃₄ N₂ O₆ : Calc.: C, 68.76; H, 6.77; N, 5.53; Found:C, 68.74; H, 7.03; N, 5.68.

EXAMPLE 64 Endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate

A mixture of 3.4 g of5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl-7-benzofurancarboxamide, 2.0 g of 10% palladium oncarbon, 0.7 ml of concentrated hydrochloric acid, and 200 ml of aceticacid were subjected to hydrogenation at a temperature of approximately25°-30° C. After hydrogen uptake ceased, the reaction mixture wasfiltered, and the filtrate concentrated in vacuo. One gram of theresidue was purified by high pressure liquid chromatography using 24%ethanol and 1% ammonium hydroxide in ethyl acetate as the eluant. Thedesired fractions were combined, concentrated in vacuo, and convertedinto the maleate salt. Recrystallization from ethanol/diethyl etherprovided 623 mg of the desired title intermediate, m.p. 210°-212° C.

Analysis for C₂₂ H₂₇ ClN₂ O₆ : Calc.: C, 58.60; H, 6.04; N, 6.21; Found:C, 58.89; H, 6.14; N, 6.42.

EXAMPLE 65

The debenzylated intermediate of Example 64 can be converted into thedesired N-alkyl derivative of this invention by treating theintermediate with the appropriate (C₁ -C₃) alkyl iodide intetrahydrofuran or isopropyl alcohol in the presence of sodiumcarbonate.

EXAMPLE 66 5-Bromo-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acid

The title intermediate was prepared in 20% yield from2-methyl-2-propenyl 5-bromo-3-(2-methyl-2-propenyl)-2-hydroxybenzoateupon heating at reflux with 90% formic acid.

Analysis for C₁₁ H₁₁ BrO₃ : Calc.: C, 48.73; H, 4.09; Found: C, 48.73;H, 4.13.

EXAMPLES 67-69

The following compounds were prepared from the correspondingbenzofurancarboxylic acids and the appropriate amine following theprocedure of Example 16.

67. Endo-5-bromo-2,2-dimethyl-2,3-dihydro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 16% yield,m.p. 185°-187° C.

Analysis for C₂₃ H₂₉ BrN₂ O₆ : Calc.: C, 54.23; H, 5.74; N, 5.50; Found:C, 54.22; H, 5.79; N, 5.47.

68. 2,2-Dimethyl-2,3-dihydro-5-fluoro-N-(1-azabicyclo[2.2.2]oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 31% yield,m.p. 199°-200° C.

Analysis for C₂₂ H₂₇ FN₂ O₆ : Calc.: C, 60.82; H, 6.26; N, 6.45; Found:C, 61.07; H, 6.22; N, 6.34.

69. Endo-5-fluoro-2,3-dihydro-2,2-dimethyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate, 16% yield,m.p. 111°-112° C.

Analysis for C₂₄ H₃₁ FN₂ O₆ : Calc.: C, 62.33; H, 6.76; N, 6.06; Found:C, 62.28; H, 6.70; N, 5.85.

Other compounds illustrative of this invention include:

Endo-5-methylthio-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide

Endo-5-methylsulfonyl-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl-7-benzofurancarboxamide

Endo-5-methylsulfinyl-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-benzofurancarboxamide

5-Methylthio-2,3-dihydro-2,2-dimethyl-N-(1-azabicyclo[2.2.2]oct-3-yl)-7-benzofurancarboxamide

5-Methylsulfinyl-2,3-dihydro-2,2-dimethyl-N-(1-azabicyclo[2.2.2]oct-3-yl)-7-benzofurancarboxamide

5-Methylsulfonyl-2,3-dihydro-2,2-dimethyl-N-(1-azabicyclo[2.2.2]oct-3-yl)-7-benzofurancarboxamide

Endo-5-methylthio-2,3-dihydro-2,2-dimethyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-7-benzofurancarboxamide

Endo-5-methylsulfinyl-2,3-dihydro-2,2-dimethyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-7-benzofurancarboxamide

Endo-5-methylsulfonyl-2,3-dihydro-2,2-dimethyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-7-benzofurancarboxamide

6-Chloro-3,4-dihydro-2,2-diethyl-N-(1-azabicyclo[2.2.2]oct-3-yl-2H-1-benzopyran-8-carboxamide

3,4-Dihydro-2,2-diethyl-N-(1-azabicyclo[2.2.2]oct-3-yl)-2H-1-benzopyran-8-carboxamide

Endo-6-chloro-3,4-dihydro-2,2-diethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2H-1-benzopyran-8-carboxamide

Endo-3,4-dihydro-2,2-diethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2H-1-benzopyran-8-carboxamide

Endo-6-chloro-3,4-dihydro-2,2-diethyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2H-1-benzopyran-8-carboxamide

Endo-3,4-dihydro-2,2-diethyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2H-1-benzopyran-8-carboxamide

6-Fluoro-3,4-dihydro-2,2-dimethyl-N-(1-azabicyclo[2.2.2]oct-3-yl)-2H-1-benzopyran-8-carboxamide

6-Chloro-3,4-dihydro-2,2-dimethyl-N-(1-azabicyclo[2.2.2]oct-3-yl)-2H-1-benzopyran-8-carboxamide

Endo-6-fluoro-3,4-dihydro-2,2-dimethyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2H-1-benzopyran-8-carboxamide

Endo-6-chloro-3,4-dihydro-2,2-dimethyl-N-(9-methyl-9azabicyclo[3.3.1]non-3-yl)-2H-1-benzopyran-8-carboxamide

Endo-6-fluoro-3,4dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2H-1-benzopyran-8-carboxamide

The compounds of Formula I of this invention are long-acting, orallyeffective specific 5-HT₃ receptor antagonists, rendering them useful forthe treatment of migraine. Because of this mechanism, the compounds ofthis invention should also be useful for treating emesis, motionsickness, ischemic bowel disease, diabetic gastric paresis, relaxationof the gastrointestinal tract for instrumentation, othergastrointestinal pain following surgery, obstetrics or as in abdominalcramps, and for treating CNS disorders such as schizophrenia andanxiety. The ability of these compounds to antagonize the effects of5-HT was assessed by their inhibition of the Von Bezold-Jarisch reflexinduced by 5-HT injected intravenously into the rat (See Paintal,Physiol. Rev. 53, 159 (1973)). When administered by the intravenousroute 15 minutes prior to the administration of 5-HT, the compounds ofthis invention were effective in inhibiting the serotonin-inducedBezold-Jarisch reflex as summarized in Table 1 below:

                  TABLE 1                                                         ______________________________________                                        Inhibition of Serotonin-induced Bezold-Jarisch Reflex in Rats                 Compound of                                                                            Percent Inhibition of Reflex in Rats (mg/kg I.V.)                    Example No.                                                                            0.03      0.01      0.003   0.001                                    ______________________________________                                        16                 0.1                                                        17       82        53        -2                                               18                 1.2                                                        19                           90      66                                       20                 16                                                         21                 87        11      0.3                                      22                 -4                                                         23                 -8                                                         24                 38        21                                               25                 83        19      10                                       26                 2                                                          27                 20                                                         28                 4                                                          29                 -4                                                         30                 67        26                                               31                 32                                                         32                 80        80      58                                       33       57        22                                                         34                 69        51      6                                        35                 31                                                         36                 76                4                                        37                 4                                                          38       51        26                                                         39       82        53        -2                                               40                 67        14      3                                        41                 -1                                                         49                 89        40                                               50                 -3                                                         52                           -7                                               53                           93      50                                       54                 94        84                                               55                           88                                               56                 89        25                                               57                 3                                                          58                 71                                                         60                           87      25                                       61                 91        30                                               62                 54                                                         ______________________________________                                    

These compounds may also be used as antiemetic agents. This use isexemplified by the compound of Example 19 which effectively blockedcisplatin-induced emesis in dogs with an i.v. ED₅₀ of 35.6 mcg/kg. Since5HT₃ receptors are prevalent in the GI tract, other potential usesinclude other diseases of the gastrointestinal tract, such as ischemicbowel, esophageal reflux, etc.

The compounds of Formula I of this invention may be administered byvarious routes including the oral, rectal, transdermal, subcutaneous,intravenous, intramuscular, or intranasal routes. The compounds areusually employed in the form of pharmaceutical compositions. Suchcompositions are prepared in a manner well known in the pharmaceuticalart and comprise at least one active compound. Accordingly, theinvention includes a pharmaceutical composition comprising as activeingredient a compound of Formula I in combination with apharmaceutically acceptable carrier, diluent, or excipient.

In making the compositions of the present invention, the activeingredient will usually be mixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semi-solid or liquid material which acts asa vehicle, excipient or medium for the active ingredient. Thus, thecomposition can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing forexample up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions andsterile packaged powders.

Some examples of suitable carriers, excipients, and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,calcium phosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water,syrup, methyl cellulose, methyl- and propyl-hydroxybenzoates, talc,magnesium stearate and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents or flavoring agents. Thecompositions of the invention may, as is well known in the art, beformulated so as to provide quick, sustained or delayed release of theactive ingredient after administration to the patient.

The compositions usually contain active ingredient from about 1% toabout 95% by weight and are preferably formulated in a unit dosage form,each dosage containing from about 0.5 to about 500 mg, more usually 1 toabout 300 mg, of the active ingredient. The term "unit dosage form"refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredthereapeutic effect, in association with a suitable pharmaceuticalcarrier.

The active compounds are effective over a wide dosage range and typicaldosages per day will normally fall within the range of about 0.020 toabout 50 mg/kg of body weight. In the treatment of adult humans, a rangeof from about 0.020 to about 10 mg/kg, in single or divided doses, ispreferred. However, it will be understood that the amount of thecompound actually administered will be determined by a physician in thelight of the relevant circumstances including the condition to betreated, the choice of compound to be administered, the chosen route ofadministration, the age, weight, and response of the individual patient,and the severity of the patient's symptoms, and therefore the abovedosage ranges are not intended to limit the scope of the invention inany way.

The following formulation examples may employ as active ingredients anyof the pharmaceutical compounds of the invention. The examples areillustrative only and are not intended to limit the scope of theinvention in any way.

EXAMPLE 70

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                                                            Quantity (mg/capsule)                                     ______________________________________                                        Endo-5-chloro-2,3-dihydro-2,2-dimethyl-                                                             250                                                     N-(8-methyl-8-azabicyclo[3.2.1]-                                              oct-3-yl)-7-benzofurancarboxamide                                             (Z)-2-butenedioate                                                            Starch dried          200                                                     Magnesium stearate     10                                                     ______________________________________                                    

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

EXAMPLE 71

A tablet formula is prepared using the ingredients below:

    ______________________________________                                                            Quantity (mg/tablet)                                      ______________________________________                                        d-Endo-5-chloro-2,3-dihydro-2-ethyl-2-                                                              250                                                     methyl-7-benzofurancarboxylic                                                 acid, 8-methyl-8-azabicyclo[3.2.1]-                                           oct-3-yl ester (Z)-2-butenedioate                                             Cellulose, microcrystalline                                                                         400                                                     Silicon dioxide, fumed                                                                               10                                                     Stearic acid           5                                                      ______________________________________                                    

the components are blended and compressed to form tablets each weighing665 mg.

EXAMPLE 72

An aerosol solution is prepared containing the following components:

    ______________________________________                                                           Weight %                                                   ______________________________________                                        1-2,3-dihydro-2-methyl-N-(8-                                                                       0.25                                                     methyl-8-azabicyclo[3.2.1]oct-                                                3-yl)-7-benzofurancarboxamide                                                 hydrochloride                                                                 Ethanol              29.75                                                    Propellant 22        70.00                                                    (Chlorodifluoromethane)                                                       ______________________________________                                    

The active compound is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to -30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remaining amount of propellant. The valveunits are then fitted to the container.

EXAMPLE 73

Tablets each containing 60 mg of active ingredient are made up asfollows:

    ______________________________________                                        4-fluoro-2,3-dihydro-2,2-diethyl-                                                                       60 mg                                               7-benzofurancarboxylic acid, 8-                                               methyl-8-azabicyclo[3.2.1]oct-3-yl                                            ester lactobionate                                                            Starch                    45 mg                                               Microcrystalline cellulose                                                                              35 mg                                               Polyvinylpyrrolidone      4 mg                                                (as 10% solution in water)                                                    Sodium carboxymethyl starch                                                                             4.5 mg                                              Magnesium stearate        0.5 mg                                              Talc                      1 mg                                                Total                     150 mg                                              ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50°-60° C. and passes through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate and talc, previouslypassed through a No. 60 mesh U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yield tabletseach weighing 150 mg.

EXAMPLE 74

Capsules each containing 80 mg of medicament are made as follows:

    ______________________________________                                        2,3-dihydro-2,2,5-trimethyl-                                                                           80 mg                                                N-(8-ethyl-8-azabicyclo[3.2.1]-                                               oct-3-yl)-7-benzofurancarboxamide                                             (Z)-2-butenedioate                                                            Starch                   59 mg                                                Microcrystalline cellulose                                                                             59 mg                                                Magnesium stearate       2 mg                                                 Total                    200 mg                                               ______________________________________                                    

The active ingredient, cellulose, starch and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

EXAMPLE 75

Suppositories each containing 225 mg of active ingredient are made asfollows:

    ______________________________________                                        Endo-2,3-dihydro-2,2-dimethyl-N-                                                                      225 mg                                                (8-methyl-8-azabicyclo[3.2.1]-                                                oct-3-yl)-5-benzothiophenecar-                                                boxamide                                                                      Saturated fatty acid    2,000 mg                                              glycerides to                                                                 ______________________________________                                    

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

EXAMPLE 76

Suspensions each containing 50 mg of medicament per 5 ml dose are madeas follows:

    ______________________________________                                        Endo-4-chloro-2,3-dihydro-2,2-                                                                         50 mg                                                dimethyl-N-(8-methyl-8-azabicyclo-                                            [3.2.1]oct-3-yl)-indolecar-                                                   boxamide                                                                      Sodium carboxymethyl cellulose                                                                         50 mg                                                Syrup                    1.25 ml                                              Benzoic acid solution    0.10 ml                                              Flavor                   q.v.                                                 Color                    q.v.                                                 Purified water to        5 ml                                                 ______________________________________                                    

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethylcellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor and color are diluted with some of thewater and added, with stirring. Sufficient water is then added toproduce the required volume.

We claim:
 1. A compound of the formula ##STR9## wherein m is 1; E is O;and R₁ is halo.
 2. The compound of claim 1 which is5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylic acid.